1. Field of the Invention
The present invention relates to stable glutamine derivatives and their use in rehydration and nutrition therapy.
2. Discussion of the Background
Glutamine, the chief metabolic fuel of the small intestine, is an amino acid which cotransports Na.sup.+ across the enterocyte brush border membrane. It is known to be the major bowel nutrient and energy source and has been used in intravenous solutions to improve nitrogen balance, inhibit protein breakdown, stimulate the growth of epithelial cells, and reduce intestinal villous atrophy.
Additionally, various researchers have shown that glutamine stimulates the absorption of sodium and chloride and has been tried in oral rehydration solutions to reduce cholera diarrhea.
Viral enteritis is a leading cause of diarrhea in infants and toddlers less than 2 years old. Each year in the United States, about 22,000 infants are hospitalized for treatment of rotavirus-induced dehydration. Central to the pathophysiology of diarrhea in transmissible gastroenteritis (TGE), which is one experimental model of viral enteritis, are a number of intestinal abnormalities, including impaired glucose and amino acid-coupled Na.sup.+ transport, defective NaCl absorption, diminished disaccharide hydrolysis, and reduced mucosal absorptive surface.
In a majority of cases, diarrheal disease morbidity and mortality is due to dehydration. The primary effect seen is the loss of fluid and electrolytes in diarrheal stools. An immediate effect in treatment of dehydration can be achieved by early oral administration of sugar (glucose) and electrolyte solution and continued feeding. However, conventional therapy by administration of oral rehydration formulations does not reduce stool volume or the duration of diarrhea. Thus, modifications of the oral rehydration therapy are needed to actually reduce stool volume or speed the recovery of normal mucosal function, which in turn would substantially enhance the acceptability and effectiveness of such therapy.
The physiological principle of oral rehydration therapy was first observed by Schultz and Curran (Physiology Review, 50:637-718 (1970)). They demonstrated the intestinal cotransport of sodium with glucose. Others have demonstrated the active transport of organic compounds by the small intestine which, when coupled with sodium absorption, enhances the absorption of water and other salts. (See Lima et al, Bailliere's Clinical Tropical Medicine and Communicable Diseases, 3:627-636 (1988) and Soares et al, Brazilian Journal of Medical and Biological Research, 24:111-113 (1991)).
The effects of organic compounds on salt and water absorption were first applied successfully to the treatment of patients with cholera and thereafter it was shown experimentally that the salt-substrate cotransport was substantially intact in cholera patients and that oral therapy with sodium, chloride, potassium, bicarbonate and glucose in the same solution could restore and maintain normal blood volume and electrolyte concentrations.
Organic molecules such as D-hexoses, neutral amino acids, dipeptides and tripeptides of neutral amino acids, and water-soluble vitamins can also enhance sodium absorption, followed by water absorption from the small intestine. The present inventors have previously shown the efficacy of glutamine in intestinal sodium absorption. (Lima et al, Brazilian J. Med. Biol. Res., 25:637-640 (1992)). However, the greatest limitation to the oral use of glutamine is its instability and tendency to degrade in water and acid, conditions which are found in the stomach.
Bone marrow transplantation is being increasingly used in the treatment of hematologic malignancies. Patients undergoing bone marrow transplantation lose body protein because of the catabolic effects of chemotherapy, total body irradiation, and graft-versus-host disease. In addition, gastrointestinal toxicity often limits the consumption and absorption of enteral nutrients. Infectious complications also remain a major cause of morbidity in these patients. Infection accelerates protein loss, and protein-calorie malnutrition may decrease host resistance to microbial invasion.
Parenteral nutrition is known to attenuate such protein losses and may prevent complications associated with malnutrition. Despite routine use in many centers, parenteral nutrition is also, unfortunately, associated with an increased incidence of infection in patients receiving chemotherapy with or without irradiation, and also in those receiving allogeneic bone marrow transplantation. Further, despite conventional nutritional support, these patients still suffer from markedly negative nitrogen balance.
Modification of amino acid formulations may improve the clinical and metabolic efficacy of parenteral nutrition. Notably absent in all commercially available parenteral nutrient solutions is glutamine, because it has a shorter shelf-life than the commonly used amino acids and has been considered a nonessential amino acid. However, during catabolic states, glutamine concentrations in intracellular pools (primarily skeletal muscle) fall rapidly. This reduction in glutamine occurs due to use of glutamine for renal ammoniagenesis and as an oxidizable fuel for stimulated lymphocytes and macrophages and intestinal mucosal cells. Glutamine-enriched parenteral or enteral nutrition has been shown to enhance nitrogen balance, attenuate intestinal mucosal damage, decrease bacteremia, and improve survival after irradiation or chemotherapy when compared with glutamine-free nutrition. Limited clinical studies in postoperative patients have shown improved nitrogen retention with glutamine-enriched parenteral feeding. The clinical safety of L-glutamine added as a component of balanced parenteral nutrient solutions has recently been documented. (See Ziegler et al, Annals of Internal Medicine, 116:821-828 (1992) and references cited therein).
Masaki et al, U.S. Pat. No. 4,987,123, disclose the use of L-alanine, L-glutamine, L-alanyl-L-glutamine and salts thereof in the treatment of hepatic disorders. However, there is no indication as to the efficacy of using glutamine derivatives in treatment of disorders associated with dehydration or with nitrogen imbalance.
While the above-noted studies have shown the efficacy of Glutamine in rehydration and nutrition therapies, the instability of glutamine in the digestive tract has diminished its usefulness. Accordingly, there is needed a method for administration of glutamine to patients which will provide effective treatment in oral rehydration therapy and nutrition therapy, while overcoming the difficulties of instability in an acidic environment.